Process for preparing (4R,12aS)-N-(2,4-difluorobenzyl)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12A-hexahydro-2H-pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide

ABSTRACT

The present invention relates to the preparation of (4R,12aS)-N-(2,4-difluorobenzyl)-7-methoxy-4 -methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide of the formula VIIa:

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. Ser. No.14/513,265, filed on Oct. 14, 2014, which is a divisional application ofSer. No. 13/636,237, now U.S. Pat. No. 8,889,877, filed on Nov. 13,2012, which was filed under 35 USC 371 as a United States National PhaseApplication of International Patent Application Serial NumberPCT/US2011/029369 filed Mar. 22, 2011, which claims priority from U.S.Provisional Application Ser. No. 61/316,421 filed Mar. 23, 2010.

FIELD OF THE INVENTION

The present invention relates to the preparation of carbamoylpyridonederivatives and intermediates which are useful as HIV integraseinhibitors.

BACKGROUND OF THE INVENTION

Compounds having HIV integrase inhibitory activity are described in WO2006/116764 (corresponding to U.S. Ser. No. 11/919,386 assigned toShionogi & Co. Ltd.). The compounds are disclosed as polycycliccarbamoylpyridone deriviatives. Processes for making them are alsodisclosed. Among the examples of these compounds, the followingpolycyclic carbamoylpyridone derivatives are included:

The processes disclosed for preparing these compounds are quite arduous,involving as many as 14 steps. It would therefore be an advance in theart to find ways of making these compounds with greater efficiency.

SUMMARY OF THE INVENTION

The present invention provides an improved process for preparing thefollowing compounds:

In one aspect, the present invention is a method comprising contactingmethyl3-{[2,2-bis(methyloxy)ethyl]amino}-2-[(methyloxy)acetyl]-2-propenoate(formula I):

with an oxalate ester of formula II:

in the presence of M⁺ ⁻OR, where R is alkyl, aryl, or benzyl; and M⁺ isan alkali metal cation; to form a pyridinone of formula III:

In a second aspect, the present invention method comprising selectivelyhydrolyzing a pyridinone of formula III:

where R is alkyl, aryl, or benzylwith a selective hydrolyzing reagent to form a pyridinone carboxylicacid of formula IV where R is alkyl, aryl, or benzyl:

with greater than 90% selectivity.

In a third aspect, the present invention is a method comprisingcontacting a compound of formula VII:

with a magnesium or lithium cation and a nucleophilic anion to form acompound of formula VIII:

In a fourth aspect, the present invention is a compound selected fromthe group consisting of:

In a fifth aspect, the present invention is a process comprisingcontacting a compound of formula IV where R is alkyl, aryl, or benzyl:

with acetic acid and a catalytic amount of a strong protic acid to forma pyridinone carboxylic acid aldehyde of formula V where R is alkyl,aryl, or benzyl:

The process of the present invention is useful for the preparation ofcompounds with HIV integrase inhibitory activity.

DETAILED DESCRIPTION OF THE INVENTION

The following schematic illustrates a general process for thepreparation of the compound of formula VIII,((3S,11aR)—N-[(2,4-difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-α]pyrido[1,2-d]pyrazine-8-carboxamide).

In the above schematic, 4-Methoxyacetoacetate is contacted with DMFDMA(N,N-dimethyl-1,1-bis(methyloxy)methanamine) under conditions sufficientto form methyl 3-(dimethylamino)-2-[(methyloxy)acetyl]-2-propenoate.Reaction of this intermediate with aminoacetaldehyde dimethyl acetalresults in the formation of methyl3-{[2,2-bis(methyloxy)ethyl]amino}-2-[(methyloxy)acetyl]-2-propenoate(I).

Compound I is then contacted with oxalate ester (II) in the presence ofM⁺ ⁻OR to form pyridinone (III). Each R is C₁-C₅-alkyl, aryl, or benzyl;M⁺ is an alkali metal cation such as lithium, sodium, or potassium.Preferably, the alkali metal cation is lithium and the R group of theoxalate ester is the same as the R group from M⁺ ⁻OR. Preferably R is aC₁-C₅-alkyl, especially a C₁-C₂-alkyl. Particularly preferred oxalateesters are dimethyl ethanedioate and diethyl ethanedioate. Particularlypreferred alkali metal alkoxides are lithium methoxide and lithiumethoxide. Preferably, when the oxalate ester is dimethyl ethanedioate,the alkali metal alkoxide is lithium methoxide. Preferably, when theoxalate ester is diethyl ethanedioate, the alkali metal alkoxide islithium ethoxide.

Pyridinone (III) is selectively hydrolyzed with LiOH to form pyridinonecarboxylic acid (IV). Surprisingly, the methyl ester at the 5-positionof pyridinone (III) is hydrolyzed with at least 90% selectivity over theester at the 2-position.

Pyridinone carboxylic acid (IV) is contacted with acetic acid and acatalytic amount of a strong protic acid to form pyridinone carboxylicacid aldehyde (V). Examples of suitable strong protic acids includemethanesulfonic acid, sulfuric acid, toluene sulfonic acid, andhydrochloric acid. Aldehyde (V) is then contacted with(2S)-2-amino-1-propanol to form((3S,11aR)-3-methyl-6-(methyloxy)-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-α]pyrido[1,2-d]pyrazine-8-carboxylicacid) (VI).

Compound VI is contacted with 2,4-difluorobenzylamine under couplingconditions to form(3S,11aR)—N-[(2,4-difluorophenyl)methyl]-3-methyl-6-(methyloxy)-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-α]pyrido[1,2-d]pyrazine-8-carboxamide(VII).

Finally, compound VII is demethylated with a Lewis acid to form theproduct(3S,11aR)—N-[(2,4-difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-α]pyrido[1,2-d]pyrazine-8-carboxamide(VIII). Examples of suitable Lewis acids include magnesium, lithium, andcalcium salts, as well as boron trihalides and trialkylsilyl halides.Preferred Lewis acids are magnesium and lithium salts. Magnesium saltsinclude salts such as magnesium chloride, magnesium bromide, magnesiumiodide, and magnesium sulfide. Lithium salts include salts such aslithium chloride, lithium bromide, lithium iodide, and lithium sulfide.Lithium bromide is preferred.

Alternatively, and in another aspect of the present invention, compoundV can be contacted with (3R)-3-amino-1-butanol to form a compound offormula VIa:

Compound VIa can be reacted with 2,4-difluorobenzylamine under couplingconditions to form a compound of formula VIIa:

Compound VIIa can be demethylated with MgX_(n) or LiX_(n) (wherein X isa halide, e.g., Br, Cl, F, or I) to form the compound of VIIIa:

EXAMPLES

The following example illustrates the process of the present invention.Solvents and reaction conditions are not intended to limit the scope ofthe invention. Starting materials are known in the art and are readilyprepared or commercially available. Preferably, chemicals employed inthe examples were obtained commercially (from Aldrich®, for example).

A.1-[2,2-Bis(methyloxy)ethyl]-5-(methyloxy)-6-[(methyloxy)carbonyl]-4-oxo-1,4-dihydro-3-pyridinecarboxylicacid

A mixture of methyl 4-methoxyacetoacetate (20 mL) and DMFDMA (24 mL) wasstirred at room temperature for 1.5 h. The reaction mixture was dilutedwith MeOH (50 mL) and aminoacetaldehyde dimethyl acetal (16.7 mL) wasadded. The mixture was stirred for 1 h at room temperature,concentrated, and then diluted with MeOH (113 mL). Dimethyl oxalate(45.66 g) was charged followed by portion-wise addition of LiH (2.15 g)while maintaining the reaction temperature below 25° C. The reactioncontent was heated to 40° C. for 14 h. The reaction mixture was cooledto −5° C. and LiOH (14.82 g) was added while maintaining the reactiontemperature below 5° C. When addition was complete, the mixture wasstirred for a further 2 h at 3-5° C. for 1 h. The reaction mixture wasquenched with aqueous HCl (2 N, 367 mL), maintaining the reactiontemperature below 5° C. When addition was complete, EtOAc (450 mL) wasadded and the mixture was warmed to 20° C. The reaction mixture wasfiltered and the aqueous layer discarded. Water (225 mL) was added andthe organic layer was removed under reduced pressure. The product wascollected by filtration and dried in a vacuum oven overnight at 50° C.The product was obtained as a solid.

B.(3S,11aR)-3-Methyl-6-(methyloxy)-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxylicacid

1-[2,2-bis(methyloxy)ethyl]-5-(methyloxy)-6-[(methyloxy)carbonyl]-4-oxo-1,4-dihydro-3-pyridinecarboxylicacid (22.54 g) was dissolved in 220 mL of CH₃CN. HOAc (20 mL) andCH₃SO₃H (1.4 mL) were added at room temperature and the mixture washeated to 58-65° C. for 19.5 h. Alaninol (7.511 g) in CH₃CN (15 mL) wasadded slowly and the resultant mixture was stirred at 64° C. for 18.5 h.The mixture was concentrated, and the residue was redissolved in CH₂Cl₂(170 mL). HCl (1 N, 170 mL) was added and the layers were separated. Theaqueous layer was extracted with CH₂Cl₂ (170 mL×2) and the organiclayers were combined and concentrated. MeOH (50 mL) was added and theresultant mixture was again concentrated. MeOH (80 mL) was added and theresultant mixture was heated at reflux for 4 h, gradually cooled to 20°C. and held at 20° C. for 15 h. The product was collected by filtrationand dried under vacuum.

C.(3S,11aR)—N-[(2,4-Difluorophenyl)methyl]-3-methyl-6-(methyloxy)-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide

(3S,11aR)-3-Methyl-6-(methyloxy)-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxylicacid (3.00 g) and 1,1′-carbonyldiimidazole (CDI) (2.15 g) were slurriedin 1,2-dimethoxyethane (DME) (30 mL). The mixture was heated to 80° C.for 1 h. The resulting solution was cooled to 20° C., then treated with2,4-difluorobenzylamine (1.45 mL). After stirring for 1 h, the mixturewas quenched with water (30 mL) and DME was removed under reducedpressure. The product was collected by filtration and dried in a vacuumoven overnight at 50° C. The product was obtained as a solid.

D.(3S,11aR)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide

(3S,11aR)—N-[(2,4-Difluorophenyl)methyl]-3-methyl-6-(methyloxy)-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-α]pyrido[1,2-d]pyrazine-8-carboxamide(193.1 mg) was dissolved in CH₃CN (4 mL) and MgBr₂ (206.3 mg) was added.The mixture was heated to 50° C. for 2 h and quenched with HCl (0.2 N,10 mL). The mixture was diluted with CH₂Cl₂ and pH further adjusted to˜1. The aqueous layer was extracted with CH₂Cl₂ (10 mL×2). The combinedorganic layers were dried and concentrated to afford the product.

Alternatively, the demethylation can be carried out with LiBr:(3S,11aR)—N-[(2,4-Difluorophenyl)methyl]-3-methyl-6-(methyloxy)-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-α]pyrido[1,2-d]pyrazine-8-carboxamide(8.609 g) was dissolved in THF (90 mL) and LiBr (3.942 g) was added. Themixture was heated to reflux for 12 h and quenched with H₂SO₄ (0.5 M,94.467 g). The resultant suspension was stirred at 20° C. for 2 h andfiltered. The solid product was re-slurried in water-THF (50 mL-50 mL)at 20° C. for 2 h. The product was collected by filtration, rinsed withwater-THF (1-1, 30 mL), and dried under vacuum to afford the product.

What is claimed is:
 1. A process for the preparation of a compound offormula VIIa:

comprising contacting a compound of formula VIa:

with 2,4-difluorobenzylamine.